At the other end of the spectrum, Kashiwagi and Jain [28] described radiosensitization in glioma xenografts through the normalizing effects of NOS inhibition on the tumor vasculature. The cytotoxicity of NO below a certain threshold is consistent with the assumption that lower concentrations of NO reduce

signal transduction below a physiological baseline, leading to a loss of the aberrant induction of proangiogenic [5] signaling [29] networks that promote malignant progression (Figure 3). This emerging background of conflicting preclinical evidence that both anti-NO–centered and pro-NO–centered therapeutic strategies are therapeutically effective has resulted TSA HDAC nmr in the initiation of human clinical trials with both NO donors and NO inhibitors such as nitroglycerin (NTG), N-nitro-l-arginine (l-NNA), and RRx-001 to push the tumor out of its “hormetic comfort zone. As an operational definition, epigenetics comprises heritable alterations Nintedanib cell line in gene expression not due to changes in the underlying DNA sequence. These epigenetic alterations may involve changes in DNA methylation patterns, altered mRNA expression, and modifications of the histones around which the DNA is wrapped. NO has been shown to be an epigenetic factor on the basis of its ability to influence DNA methylation, microRNA and histone modification in normal [30] as well as tumor tissues

[31], acting directly [32] or through induction of NOSs [33]. As a consequence of these mechanisms, therapies that result in global epigenetic changes in the tumor microenvironment or ecosystem [34] due to selective delivery or inhibition of NO may alter the tumor phenotype in such a way Cobimetinib mouse that it becomes sensitized or resensitized to subsequent chemotherapy, leading to improved overall survival [31], [32] and [35]. Furthermore, it is possible that some epigenetic effects (e.g., DNA methylation, histone modifications, and

microRNAs), might have immunomodulatory effects and could potentially affect immune cell and cytokine function in the tumor microenvironment in such a way as to facilitate antitumor immune responses. In response to DNA damage, the p53 tumor suppressor protein activates checkpoint-mediated G1/S arrest or apoptosis to prevent proliferation of cells with a damaged genome. p53 transcriptionally activates downstream genes such as p21, which bind to and inhibit several cyclin dependent kinase complexes. p53 is also implicated in the induction of cellular senescence, also through p21 gene activation. An increase in NO levels may lead to tumor senescence, characterized by p53 activation, through p53 nuclear retention [35] and the secretion of proinflammatory cytokines such as Interleukin 6 (IL-6) and IL-8, which stimulate the immune system.